A major limitation with most current medical therapies for inflammatory bowel disease (IBD) is the indiscriminant immunosuppressive effect of these drugs. We have recently demonstrated the ability to palliate the progression of colitis in a mouse dextran sodium sulfate (DSS) model through blockage of signaling via the type 1a (AT1a) receptor of the renin-angiotensin system. The intervention leads to significant reduction in the clinical severity of colitis, improvement in histologic scores and a down-regulation in the expression of proinflammatory cytokines. The AT1a receptor is a specific receptor which triggers the NF?B cascade, ultimately resulting in apoptosis. It is also specific for the initiation of fibrosis formation and has been shown to be selectively overexpressed in the DDS model of IBD. Hence, pursuing the AT1a receptor antagonists has the potential to result in a potent and selective therapy for IBD. Although this treatment shows tremendous potential in treating IBD, a major consequence of the AT1a blockade is systemic hypotension. To circumvent this problem, we have selected a series of prototype drugs that display a high capacity for blockage of AT1a receptor signaling, but show poor intestinal permeability. Preliminary pre-clinical studies of these prototype drugs demonstrate very high efficacy in the treatment of colitis when delivered via the transanal route, without systemic hemodynamic side-effects. Due to their poor oral availability and their strong AT1a receptor binding, we theorize that these AT1a receptor antagonists would be good candidates for oral delivery. We propose to synthesize a series of AT1a receptor antagonists and test their efficacy in cell based assays. These candidates will be tested for their absorption potential along the entire gastrointestinal tract using standard rodent models of intestinal permeability and bioavailability. Finally, we will determine the efficacy of the potential lead compounds in a preclinical murine model of IBD. The goal of this proposal is to develop an entirely new type of drug therapy for IBD using the AT1a antagonists, which focuses on local control of the inflammatory response, without systemic side effects. Since this class of drugs is not currently used for IBD, this approach potentially could be used as either single therapy, or added to current regimens, allowing for reduced systemic immune suppression. Findings from these studies could lead to a unique strategy to treat inflammatory bowel disease. TSRL has formed a collaboration with Drs. Dan Teitelbaum, Scott Larsen and Hollis Showalter of the University of Michigan to address this problem. The team brings a wealth of experience and expertise in the areas of medicinal chemistry, inflammatory bowel disease pharmacology and oral absorption strategies to the program. PUBLIC HEALTH RELEVANCE: This phase I SBIR project is seeking to develop novel medicines for the treatment of inflammatory bowel disease, a debilitating disease that is currently only treatable with drugs which cause significant side effects. The goal is the development of a medicine that can be easily taken by mouth both during a flare-up of the disease as well as a maintenance treatment.